This invention relates to a new and useful process for preparing two valuable asymmetric spiro-hydantoin ring compounds. More particularly, it is concerned with an improved chemical process for synthesizing (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione (sorbinil) and its (2R)-methyl derivative (2-methylsorbinil), which are of especial value in the field of medicinal chemistry in view of their known ability to act as aldose reductase inhibitors and thereby effectively control certain chronic diabetic complications, such as diabetic cataracts and neuropathy, etc. The invention also includes within its scope various novel compounds which are useful as intermediates in the process.
According to the prior art, sorbinil was first reported as d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione by R. Sarges in U.S. Pat. No. 4,130,714. It was originally prepared by a multi-step process which essentially involved condensing 6-fluoro-4-chromanone with potassium cyanide and ammonium carbonate to form the corresponding racemic precursor, followed by resolution of the latter dl-compound with l-brucine. The 6-fluoro-4-chromanone used in the process was ultimately derived from p-fluorophenol in a series of steps which first involved converting the latter compound to .beta.-(p-fluorophenoxy)propionic acid according to the method described by G. C. Finger et al. in the Journal of the American Chemical Society, Vol. 81, p.94 (1959), followed by intramolecular condensation of the latter intermediate acid in the presence of polyphosphoric acid to effect ring-closure to the desired chromanone compound.
Later developments in the overall method of production then finally gave a process for producing sorbinil which involved the following steps, viz., (1) p-fluorophenol was first converted to .beta.-(p-fluorophenoxy)propionitrile by treatment with acrylonitrile in the presence of Triton B; (2) the nitrile intermediate was then converted to .beta.-(p-fluorophenoxy)propionic acid by means of hydrochloric acid; (3) .beta.-(p-fluorophenoxy)propionic acid was then condensed in the presence of concentrated sulfuric acid at 50.degree. C. to afford 6-fluoro-4-chromanone; (4) the latter compound was thereafter condensed with potassium cyanide and ammonium carbonate in ethanol under standard Bucherer-Berg conditions to give the racemic precursor of sorbinil, which is called dl-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione; (5) the latter racemic spiro-hydantoin was then hydrolyzed with aqueous sodium hydroxide to the corresponding spiro-amino acid, which is called 4-amino-6-fluorochroman-4-carboxylic acid; (6) the latter acid, which can not be conveniently isolated in the process, was then treated in situ with sodium or potassium cyanate (after first adjusting the pH of the aqueous solution) in order to convert the amino acid to the corresponding hydantoic acid, which is called 6-fluoro-4-ureidochroman-4-carboxylic acid; (7) the latter hydantoic acid was then resolved according to the method described by B. W. Cue, Jr. et al. U.S. Pat. No. 4,435,578 by treatment with l-(-)-ephedrine in aqueous methanol to form the l-(-)-ephedrine salt of (4S)-6-fluoro-4-ureidochroman-4-carboxylic acid; and (8) the latter crystalline salt was thereafter converted to sorbinil by heating the diastereoisomer in glacial acetic acid to effect conversion to the desired (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione.
As regards the (2R)-methyl derivative of sorbinil, this compound was first reported by K. Ueda et al. in Published U.K. Patent Application No. GB 2,080,304A, where it was called d-6-fluoro-2-methyl-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione. It was prepared in a somewhat analogous manner to the original method of R. Sarges as outlined above, starting from p-fluorophenol and proceeding through the 6-fluoro-2-methyl-4-chromanone intermediate which was prepared by condensing p-fluorophenol with crotonic acid in the presence of polyphospheric acid. The resulting 6-fluoro-2-methyl-4-chromanone was then condensed with potassium cyanide and ammonium carbonate in the usual manner to ultimately afford dl-6-fluoro-2-methyl-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione in the form of the desired diastereoisomer. Resolution of the latter dl-compound with an aqueous quinine methohydroxide solution then finally gave the desired d-6-fluoro-2-methyl-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, which is more properly called (4S)(2R)-6-fluoro-2-methyl-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione in the present system of nomenclature.